The present invention relates to novel compounds useful as A.sub.1 adenosine receptor antagonists.
Adenosine receptors are involved in a vast number of peripheral and central regulatory mechanisms such as, for example, vasodilation, cardiac depression, inhibition of lipolysis, inhibition of insulin release and potentiation glucagon release in the pancreas, and inhibition of neurotransmitter release from nerve endings.
In general, adenosine receptors can be divided into two main classes, A.sub.1 receptors which can inhibit, and A.sub.2 receptors which can stimulate adenylate cyclase activity. One of the best known classes of adenosine receptor antagonists are the xanthines which include is caffeine and theophylline. See e.g., Muller et al., J. Med. Chem. 33: 2822-2828 (1990). In general, many of these antagonists often suffer from poor water solubility, and low potency or lack of selectivity for adenosine receptors. Additionally, selective analogues of adenosine receptor antagonists have been developed through the "functionalized congener" approach. Analogues of adenosine receptor ligands bearing functionalized chains have been synthesized and attached covalently to various organic moieties such as amines and peptides. Attachment of the polar groups to xanthine congeners has been found to increase water solubility. Nonetheless, such developments have yet to fully address problems associated with potency and selectivity. More recently Jacobson et al. J. Med. Chem. 35: 408-422 (1992) has proposed various derivatives of adenosine and theophylline for use as receptor antagonists. The article discloses that hydrophobic substituents are able to potentially enhance affinity. However, it is also acknowledged that such substituents may result in a decrease in solubility thus rendering the antagonists less soluble in vivo. In confronting these problems, Jacobson et al. indicates that a dipropyl substitution at the 1 and 3 positions of theophylline allows desirable affinity at A.sub.1 receptors. It is also stated that substitutions at the 7-position are typically not favorable.
It is an object of the present invention to therefore provide compounds useful as A.sub.1 adenosine receptor antagonists which display high potency and affinity levels, along with water solubility.